Suppression of human neutrophil functions by tetracyclines

Gabler, W. L.; Creamer, Howard R.

doi:10.1111/j.1600-0765.1991.tb01626.x

Cited by 151 publications

(86 citation statements)

References 24 publications

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“…The possible mechanisms of doxycycline-induced MMPs inhibition include direct transcriptional inhibition because of blockage of the activating protein factor-1 (Hanemaaijer et al 1998), chelation of Zn 2+ or Ca 2+ thus blocking the active site of MMPs , or blockage of MT1-MMP-induced pro-MMP activation (Lee et al 2001). Previous studies showed doxycycline has effects on neutrophil suppression (Gabler and Creamer 1991), caspase 3 inhibition and suppression of microglial activation (Jantzie et al 2005). As MMPs inhibition might be only one of the possible neuroprotective mechanisms provided by doxycycline, we would like to choose a more specific MMPs inhibitor (GM6001) to further study the neuroprotective mechanisms and the long-term effects after MMP inhibition in neonatal HI brain injury.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Chen

Hartman

Ayer

et al. 2009

Journal of Neurochemistry

109

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Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which are capable of degrading many types of extracellular matrix proteins and involved in the process of tissue remodeling in various pathologic conditions, including inflammatory diseases, tumor cell invasion, and angiogenesis. Previous studies suggest that MMPs, in particular MMP-2 and MMP-9, are deleterious in the brain after stroke (Power et al. 2003;Svedin et al. 2007). In acute stage after ischemic stroke, the effect of MMP activity is correlated to degradation of neurovascular matrix and opening of blood-brain barrier (BBB), which promotes vasogenic edema and results in neurological deficits. However, recent studies suggest that MMPs were also indicated to be involved in the repairing phase in the delayed stage after cerebral ischemia, including neuroblasts migration and neuronal plasticity (Lee et al. 2006;Zhao et al. 2006 AbstractThe present study was designed to investigate the role of matrix metalloproteinases (MMPs) in the immature brain and the long term effects of early MMPs inhibition after hypoxicischemic (HI) injury. HI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8% O 2 for 2 h) in P7 rat pups. GM6001, a broad spectrum MMPs inhibitor, was injected (50 mg/kg or 100 mg/kg) intraperitoneally at 2 h and 24 h after HI injury. Blood-brain barrier (BBB) integrity, brain edema, MMP-2/-9 activity, TIMP-1/-2 and tight junction protein (TJP) level were evaluated using IgG staining, Evan's blue extravasation, brain water content, zymography and western blot. Doxycycline, another MMPs inhibitor, was injected (10 mg/kg or 30 mg/kg) intraperitoneally at 2 h after HI, then BBB integrity and brain edema were measured at 48 h post-HI using brain water content measurement and IgG staining. The long-term effects of early MMPs inhibition (GM6001, 100 mg/ kg) were evaluated by neurobehavioral tests, body weight, and brain atrophy measurement. GM6001 attenuated brain edema and BBB disruption at the dosage of 100 mg/kg. MMP-2 activity increased at 24 h and peaked at 48 h after HI, whereas MMP-9 activity peaked at 24 h and tapered by 48 h after HI. MMP-9/-2 activities were significantly attenuated by GM6001 at 24 h and 48 h after HI. The degradation of TJPs (ZO-1 and occludin) at 48 h after HI was reversed by GM6001 treatment. Early MMPs inhibition had long-term effects that attenuated ipsilateral brain tissue loss, and improved neurobehavioral outcomes after HI. These results suggest that early MMPs inhibition with a broad-spectrum inhibitor provides both acute and long-term neuroprotection in the developing brain by reducing TJPs degradation, preserving BBB integrity, and ameliorating brain edema after neonatal HI injury. Keywords: blood-brain barrier, hypoxic/ischemic, matrix metalloproteinase, neonatal.

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Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Chen

Hartman

Ayer

et al. 2009

Journal of Neurochemistry

109

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“…Doxycycline is a semisynthetic, longacting, second-generation tetracycline which is absorbed rapidly and penetrates well into the brain and CSF (48). Doxycycline has been shown to have anti-inflammatory effects that are separate and distinct from its antimicrobial action (13,16,35,43). These effects include the reduction of cytokine release and the inhibition of MMPs (7, 38).…”

mentioning

confidence: 99%

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

et al. 2006

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Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 M in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats. Pneumococcal meningitis has a high level of mortality (up to 30%), and brain and/or cochlear damage occurs in up to 50% of the survivors (2). Inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣) and matrix metalloproteinases (MMPs), are produced during the host response to bacteria and contribute to the pathophysiology that can ultimately lead to death, brain damage, and hearing impairment (23,26,29,36). The role of cytokines and MMPs in the pathophysiology of the cochlear damage associated with pneumococcal meningitis is still unknown. However, it has been demonstrated that MMPs are constitutively expressed at high levels in the cochlea (8) and that in meningitis pneumococci and polymorphonuclear leukocytes (PMNs) extend from the cerebrospinal fluid (CSF) to the perilymph via the cochlear aqueduct (5).Tetracyclines are bacteriostatic agents with broad-spectrum antimicrobial activity (3). Doxycycline is a semisynthetic, longacting, second-generation tetracycline which is absorbed rapidly and penetrates well into the brain and CSF (48). Doxycycline has been shown to have anti-inflammatory effects that are separate and distinct from its antimicrobial action (13,16,35,43). These effects include the reduction of cytokine release and the inhibition of MMPs (7, 38). Experimental and clinical studies have indicated that treatment with doxycycline may be beneficial in inflammatory diseases associated with excessive MMP activity (7,13,35).In pneumococcal meningitis massive subarachnoid and ventricular space inflammation is triggered by the presence of bacteria in the CSF space (7,1...

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“…Algunos estudios han descrito, que a altas dosis el uso de doxiciclina puede bajar la tasa de filtración glomerular causando estados de isquemia en la arteriola eferente que puede llegar a inducir el incremento en los valores de creatinina sérica, una de las teorías es la reducción en el estrés oxidativo, disminuyendo los niveles de citoquinas e inhibición de la actividad de metaloproteinasas de matriz (5,30). Se ha determinado en diferentes estudios las propiedades antiinflamatorias e inmunomoduladoras de la doxiciclina asociadas a estos efectos (31,32).…”

Section: Ehrlichia Canis and The Effects Of Doxycycline In The Treatmentunclassified

“…One of the theories is the reduction of the oxidative stress, decreasing cytokine levels and inhibiting the activity of matrix metalloproteinases (5,30). The anti-inflammatory and immunomodulatory properties of doxycycline associated with these effects have been determined in different studies (31,32). …”

Section: Sistema Inmunementioning

confidence: 99%

Farmacocinética y efectos adversos de la doxiciclina en el tratamiento de la Ehrlichiosis: fundamentos teóricos para ensayos clínicos en caninos

Molina

et al. 2017

Rev MVZ Córdoba

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Ehrlichia canis is the causative bacterium of canine monocytic ehrlichiosis (CME), a disease of global importance in veterinary and human medicine. Several studies have addressed the therapeutic efficacy of tetracycline hydrochloride and doxycycline hyclate (HD) for the treatment of CME, however the results are still controversial. Doxycycline is the treatment of choice for canine monocytic ehrlichiosis (CME), a well characterized disease that can serve as a model for research in diseases of the Rickettsial order and tick-borne zoonoses. Although the pharmacokinetics and efficacy of the treatment in the acute and subclinical CME phases have been known for decades, some results also indicate that Ehrlichia canis may persist in clinically normal dogs, even after an extensive treatment regimen. The purpose of this review is to (major delve into/further investigate) the pharmacokinetics and side effects of doxycycline in the treatment of canine ehrlichiosis.Keywords: Blood chemistry, Ehrlichia canis, hematology, pharmacokinetics, tetracycline (Source: CAB). RESUMENEhrlichia canis es la bacteria causante de la Ehrlichiosis monocítica canina (EMC), una enfermedad de importancia global en la medicina veterinaria y humana. Varios estudios han abordado la eficacia terapéutica de hidrocloruro de tetraciclina e hiclato de doxiciclina (HD) para el tratamiento de la EMC, sin embargo los resultados obtenidos siguen siendo controvertidos. La doxiciclina es el tratamiento de elección para la EMC, enfermedad bien caracterizada que puede servir como modelo para las investigaciones en el estudio de las enfermedades del orden de los Rickettsiales y las zoonosis transmitidas por garrapatas. Aunque desde décadas atrás se conoce su farmacocinética y la eficacia en el tratamiento de la EMC en fase aguda y subclínica, algunos resultados también indican que Ehrlichia canis puede persistir en perros clínicamente normales, incluso después de un amplio régimen de tratamiento. El propósito de esta revisión es hacer un acercamiento referente a la farmacocinética y los efectos adversos de la doxiciclina en el tratamiento de la EMC.

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Suppression of human neutrophil functions by tetracyclines

Cited by 151 publications

References 24 publications

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Farmacocinética y efectos adversos de la doxiciclina en el tratamiento de la Ehrlichiosis: fundamentos teóricos para ensayos clínicos en caninos

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